The search for ways to relieve severe and chronic pain in the human animal has a long and varied history. Even today, the range of available drugs with which to reduce chronic and severe pain is very limited and such drugs often have severe side effects which reduce their effectiveness. The search for new painkillers continues to be a prime area of research and has even recently led to the investigation of the toad venom used by the Ecuadorian Indians in their poison weapons (Chemistry News, Science, 1993). Of the painkilling drugs available, the opiates remain the most useful and widely used. However, continued use of opiates invariably leads to addiction which limits their clinical usefulness.
Addiction has two components, tolerance and dependence. Tolerance is the decreased analgesic effectiveness of a drug with continued use. Its consequence is the necessity to increase the administered dose of the drug to maintain the necessary analgesic effect. In the case of the opiates, particularly morphine, the side effects of prolonged use at the very high doses that sometimes need to be given to sustain analgesia can produce life threatening results. Tolerance is an effect thus seen during the course of analgesic administration. Several drugs have been identified which potentiate (enhance) the effect of a given quantity of opiate, but these drugs can also produce serious side effects. By contrast, dependence is an effect seen only after termination of the repeated administration of a drug. Upon termination, a drug dependant subject experiences mild to severely harsh and unpleasant withdrawal symptoms. Despite the desperately recognized need for drugs which reduce tolerance and dependence and produce no unwanted side effects, the search for such drugs has, up to the time of this invention, been unsuccessful.
Despite intensive research, little has been learned about the underlying mechanisms of addiction. In fact, several opiate receptor mechanisms have been implicated which respond to different opiates each of which may have a separate mechanism responsible for addiction. The development during analgesic treatment of the duality of tolerance and dependence has been likened to a type of learning since it is experience dependant. The analogy of addiction to a learning process has led to the investigation of the relationship of recently discovered biochemical learning associated mechanisms to addiction. In particular, attention has centered on the recent recognition of the role of the excitatory amino acids (EAA) and their associated receptors in both neural plasticity and behavior. EAAs have been discovered to activate their receptors through action at allosteric sites located on the receptors.